Research on cytotoxic T cell responses to hepatitis C virus infection

细胞毒性T细胞对丙型肝炎病毒感染反应的研究

基本信息

批准号：
14370190
负责人：
IMAWARI Michio
金额：
$ 7.1万
依托单位：
Showa University (2003-2004)Jichi Medical University (2002)
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2004
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14370190/
关键词：
hepatitis C virus cytotoxic T cell interferon epitope HLA-A24

项目摘要

Hepatitis C virus (HCV) infection frequently persists, and leads to chronic hepatitis, cirrhosis, and eventually hepatocellular carcinoma. Acute HCV infection has decreased dramatically after universal use of disposable medical instruments and introduction of HCV test for blood products. Elimination of HCV from chronic hepatitis C patients became possible by interferon therapies. However there are still many patients who do not respond to the therapy. Since cytotoxic T lymphocytes (CTL) play an important role in elimination of infected viruses, the therapy that augments HCV-specific CTL responses may be effective for such patients. We developed the system that assesses CTL responses of peripheral blood to whole HCV antigens. Using the system, we found that HCV-specific CTL responses of patients treated with interferon decreased in accord with the decrease of HCV in serum, and that a temporary interruption of the therapy augmented CTL responses by stimulation with re-appeared HCV. We also attempted to identify HCV-specific CTL epitopes as many as possible for future development of HCV peptide vaccines. Using HCV peptides with HLA-A24-binding motif or overlapping peptides encompassing the whole HCV protein, we identified 16 novel HCV-specific CTL epitopes by interferon-', ELISpot assay. We also analyzed the phenotypes of HCV-specific CTL using CTL epitope peptide-HLA-A24-Ig dimers and cell surface markers, and found that HCV-specific CTL in the peripheral blood were poorly activated and differentiated variously.

丙型肝炎病毒（HCV）的感染经常持续存在，导致慢性肝炎，肝硬化，最终导致肝细胞癌。急性HCV感染在普遍使用一次性医疗仪器并引入血液产品测试后，急性HCV感染已大大减少。通过干扰素疗法可以从慢性丙型肝炎患者中消除HCV。但是，仍然有许多患者对治疗没有反应。由于细胞毒性T淋巴细胞（CTL）在消除感染病毒中起重要作用，因此增加HCV特异性CTL反应的治疗可能对此类患者有效。我们开发了评估外周血对整个HCV抗原的CTL反应的系统。使用该系统，我们发现接受干扰素治疗的患者的HCV特异性CTL反应随着血清中HCV的降低而降低，并且通过重新表达的HCV刺激治疗的暂时中断治疗增加了CTL反应。我们还试图鉴定HCV特异性的CTL表位，以使HCV肽疫苗的未来开发。使用HLA-A24结合基序的HCV肽或包含整个HCV蛋白的重叠肽，我们通过Interferon-'，ELISPOT测定法确定了16种新型HCV特异性CTL表位。我们还使用CTL表位肽-HLA-A24-Ig二聚体和细胞表面标记分析了HCV特异性CTL的表型，并发现外周血中的HCV特异性CTL被较差激活，并且分化了。